Fasting Protects Small Intestinal Stem Cells from Lethal DNA Damage: Mechanistic Insight and Preclinical Translation

项目总结/摘要 短期禁食已被证明可以提供宿主保护作用，使其免受与高剂量相关的毒性。 剂量化疗。我们发现了一种新的保护作用时，短期禁食给予小鼠与 大剂量化疗我们证明禁食小鼠24小时可对小肠（SI）产生保护作用 大剂量依托泊苷提取的干细胞我们还发现禁食24小时的小鼠存活率增加， h，然后用毒性剂量的辐射处理。我们将检验代谢变化的假设 与禁食相关的基因突变导致SI干细胞的表观遗传变化，这反过来又导致基因表达 其蛋白质产物保护SI干细胞免受致命的DNA损伤。该假设将在空腹 暴露于高剂量依托泊苷的小鼠和暴露于高剂量辐射的小鼠。我们的临床应用 将在胰腺癌的小鼠模型中评估这些发现。

Project Summary/Abstract Short-term fasting has been shown to provide host protective effects from the toxicity associated with high- dose chemotherapy. We found a novel protective effect conferred by short-term fasting when treating mice with high dose chemotherapy. We demonstrated that fasting mice for 24 h confers protection to small intestinal (SI) stem cells from high-dose etoposide. We also showed increased survival in mice that have been fasted for 24 h prior to treatment with toxic doses of radiation. We will test the hypothesis that the metabolic changes associated with fasting lead to epigenetic changes in SI stem cells, which in turn, leads to expression of genes whose protein products protect SI stem cells from lethal DNA damage. This hypothesis will be tested in fasted mice exposed to high-dose etoposide and mice exposed to high-dose radiation. The clinical applications of our findings will be evaluated in a mouse model of pancreatic cancer.